The Temporal Expression Pattern of Alpha-Synuclein Modulates Olfactory Neurogenesis in Transgenic Mice

Background Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS) under the murine Thy1 (mThy1) promoter, a model known to have a particularly high tg expression associated with impaired olfaction. Results Survival of newly generated neurons (NeuN-positive) in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF) promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex. Conclusions The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.

[1]  F. de Chaumont,et al.  Adult Neurogenesis Restores Dopaminergic Neuronal Loss in the Olfactory Bulb , 2014, The Journal of Neuroscience.

[2]  E. Masliah,et al.  α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy , 2014, Neurobiology of Aging.

[3]  R. Edwards,et al.  The Function of α-Synuclein , 2013, Neuron.

[4]  Hagen B. Huttner,et al.  Dynamics of Hippocampal Neurogenesis in Adult Humans , 2013, Cell.

[5]  G. Thiel.  How Sox2 maintains neural stem cell identity. , 2013, The Biochemical journal.

[6]  J. Winkler,et al.  Adult neurogenesis in Parkinson’s disease , 2013, Cellular and Molecular Life Sciences.

[7]  F. Gage,et al.  Role of α-Synuclein in Adult Neurogenesis and Neuronal Maturation in the Dentate Gyrus , 2012, The Journal of Neuroscience.

[8]  J. Winkler,et al.  Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein , 2012, Neuroscience.

[9]  M. Chesselet,et al.  A Progressive Mouse Model of Parkinson’s Disease: The Thy1-aSyn (“Line 61”) Mice , 2012, Neurotherapeutics.

[10]  Vincent Breton-Provencher,et al.  Newborn neurons in the adult olfactory bulb: Unique properties for specific odor behavior , 2012, Behavioural Brain Research.

[11]  E. Masliah,et al.  Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model , 2012, The European journal of neuroscience.

[12]  M. Chesselet,et al.  Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α‐synuclein , 2011, Journal of neuroscience research.

[13]  Zacharias Kohl,et al.  Neurodegenerative disease and adult neurogenesis , 2011, The European journal of neuroscience.

[14]  L. Lanfumey,et al.  Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson’s disease , 2011, Journal of Neural Transmission.

[15]  N. Hattori,et al.  Ectopic expression of α‐synuclein affects the migration of neural stem cells in mouse subventricular zone , 2010, Journal of neurochemistry.

[16]  P. Lledo,et al.  Turnover of Newborn Olfactory Bulb Neurons Optimizes Olfaction , 2009, The Journal of Neuroscience.

[17]  J. Winkler,et al.  Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha‐synuclein , 2009, The European journal of neuroscience.

[18]  Ryoichiro Kageyama,et al.  Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain , 2008, Nature Neuroscience.

[19]  M. Chesselet,et al.  Olfactory deficits in mice overexpressing human wildtype α‐synuclein , 2008, The European journal of neuroscience.

[20]  E. Masliah,et al.  Mutant α-synuclein exacerbates age-related decrease of neurogenesis , 2008, Neurobiology of Aging.

[21]  J. Winkler,et al.  α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice , 2008, The Journal of Neuroscience.

[22]  C. Freed,et al.  Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human α-Synuclein , 2008, Journal of Biological Chemistry.

[23]  Bernd J. Pichler,et al.  Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease , 2008, The Journal of Neuroscience.

[24]  F. Gage,et al.  Mechanisms and Functional Implications of Adult Neurogenesis , 2008, Cell.

[25]  R. Faull,et al.  Increased progenitor cell proliferation and astrogenesis in the partial progressive 6-hydroxydopamine model of Parkinson’s disease , 2008, Neuroscience.

[26]  C. Svendsen,et al.  Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation. , 2007, Human molecular genetics.

[27]  J. Olivo-Marin,et al.  Olfactory Discrimination Learning Increases the Survival of Adult-Born Neurons in the Olfactory Bulb , 2006, The Journal of Neuroscience.

[28]  T. Hirabayashi,et al.  Embryonic stem cell‐derived neuron models of Parkinson's disease exhibit delayed neuronal death , 2006, Journal of neurochemistry.

[29]  U. Bogdahn,et al.  Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb , 2006, Experimental Neurology.

[30]  Hongjun Song,et al.  Adult neurogenesis in the mammalian central nervous system. , 2005, Annual review of neuroscience.

[31]  P. Lledo,et al.  Integrating new neurons into the adult olfactory bulb: joining the network, life–death decisions, and the effects of sensory experience , 2005, Trends in Neurosciences.

[32]  J. Winkler,et al.  Humanes Wild-typ alpha-Synuclein vermindert die adulte Neurogenese , 2005 .

[33]  J. Winkler,et al.  Human Wild‐Type α‐Synuclein Impairs Neurogenesis , 2004 .

[34]  Jonathan Salcedo,et al.  Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein , 2004, The Journal of Neuroscience.

[35]  Philippe Amouyel,et al.  α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[36]  Christopher Gregg,et al.  Aging Results in Reduced Epidermal Growth Factor Receptor Signaling, Diminished Olfactory Neurogenesis, and Deficits in Fine Olfactory Discrimination , 2004, The Journal of Neuroscience.

[37]  S. Lindquist,et al.  Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology , 2003, Science.

[38]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[39]  Makoto Hashimoto,et al.  Transgenic Models of α‐Synuclein Pathology , 2003 .

[40]  Alan Carleton,et al.  Becoming a new neuron in the adult olfactory bulb , 2003, Nature Neuroscience.

[41]  Makoto Hashimoto,et al.  Differential neuropathological alterations in transgenic mice expressing α‐synuclein from the platelet‐derived growth factor and Thy‐1 promoters , 2002, Journal of neuroscience research.

[42]  Christelle Rochefort,et al.  Enriched Odor Exposure Increases the Number of Newborn Neurons in the Adult Olfactory Bulb and Improves Odor Memory , 2002, The Journal of Neuroscience.

[43]  J. Vincent,et al.  Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  C. Walsh,et al.  Doublecortin Is a Microtubule-Associated Protein and Is Expressed Widely by Migrating Neurons , 1999, Neuron.

[45]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[46]  U. Frey,et al.  Endogenous Serine Protease Inhibitor Modulates Epileptic Activity and Hippocampal Long-Term Potentiation , 1997, The Journal of Neuroscience.

[47]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[48]  D. Bonthron,et al.  PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model , 1991, Cell.

[49]  J. Altman,et al.  Post-Natal Origin of Microneurones in the Rat Brain , 1965, Nature.

[50]  E. Masliah,et al.  Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. , 2008, Neurobiology of aging.

[51]  E. Masliah,et al.  Human wild-type alpha-synuclein impairs neurogenesis. , 2004, Journal of neuropathology and experimental neurology.

[52]  M. Chesselet,et al.  Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  Philippe Amouyel,et al.  Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. , 2004, Lancet.

[54]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[55]  Makoto Hashimoto,et al.  Transgenic models of alpha-synuclein pathology: past, present, and future. , 2003, Annals of the New York Academy of Sciences.